DESCRIPTION (Applicant's abstract): We propose planning multicenter randomized controlled vials that will test the hypotheses that (1) dichlorphenamide (DCP) and acetazolamide (ACZ) will decrease attacks of weakness in hypokalemic periodic paralysis (hypoKPP); and hyperkalemic periodic paralyses (hyperKPP); (2) DCP will improve strength to a greater extent than ACZ or placebo in both periodic paralyses (PP); and (3) that DCP and ACZ will improve quality of life in both types of PP. Secondary aims are to: (1) address additional therapeutic issues in the muscle channelopathies: the importance of long-term treatments as a means of preventing progressive interattack weakness, and the long-term safety and tolerability of DCP and ACZ; (2) better define the pathophysiology of the PP; (3) examine genotype/phenotype correlations that will relate mutations in specific portions of channels to clinical manifestations of the diseases; (4) define the mechanism(s) of action of DCP and ACZ. Initial DCP trials in PP showed marked benefit for attack prevention in both hypoKPP and hyperKPP. Since those trials were initiated, the specific molecular defects have been defined for most PP. This new information and the data from the first trials will be the underpinnings for a new multicenter trial that will be planned with this grant including: (1) establishing the reliability of methods to quantitate progressive but fluctuating weakness; (2) complete clinical characterization of patients; (3) molecular characterization of cases; (4) strategies for recruitment of sufficient cases; (5) companion in vitro expression studies of mutant diseases. The 12 participating centers have worked together for more than 4 years providing reasonable certainty that we can implement a novel study design, establish precise, reliable testing methods, and create the needed recruitment strategies. The planned trials will: (1) develop standard treatments for the PP; (2) defend recommendations for long-term treatments in PP; (3) lay the groundwork for broader insight into channel dysfunction in the PP and a large number of neuromuscular and CNS diseases. (4) be part of the developing framework of the multicenter Muscle Study Group.